A Neuronal Hub Binding Sleep Initiation and Body Cooling in Response to a Warm External Stimulus

Abstract

SummaryMammals, including humans, prepare for sleep by nesting and/or curling up, creating microclimates of skin warmth. To address whether external warmth induces sleep through defined circuitry, we used c-Fos-dependent activity tagging, which captures populations of activated cells and allows them to be reactivated to test their physiological role. External warming tagged two principal groups of neurons in the median preoptic (MnPO)/medial preoptic (MPO) hypothalamic area. GABA neurons located mainly in MPO produced non-rapid eye movement (NREM) sleep but no body temperature decrease. Nitrergic-glutamatergic neurons in MnPO-MPO induced both body cooling and NREM sleep. This circuitry explains how skin warming induces sleep and why the maximal rate of core body cooling positively correlates with sleep onset. Thus, the pathways that promote NREM sleep, reduced energy expenditure, and body cooling are inextricably linked, commanded by the same neurons. This implies that one function of NREM sleep is to lower brain temperature and/or conserve energy.

Activation of Preoptic GABAergic or Glutamatergic Neurons Modulates Sleep-Wake Architecture, but Not Anesthetic State Transitions

“…However, despite biological plausibility and compelling correlative data, there have been no causal investigations to date that demonstrate a role for discrete neuronal subpopulations in the preoptic area of the hypothalamus in the mechanism of general anesthesia. Additionally, the median preoptic nucleus (MnPO) of the hypothalamus is critical for both sleep generation and the regulation of sleep homeostasis [9][10][11][12], but its influence on the anesthetized state remains virtually unexplored. In this study, we tested the hypothesis that activation of neuronal subpopulations within the preoptic area of the hypothalamus that promote sleep or wakefulness would modulate the entry to or exit from general anesthesia induced by isoflurane, a potent halogenated ether in common clinical use.…”

An Excitatory Circuit in the Perioculomotor Midbrain for Non-REM Sleep Control

“…For example, activation of gamma aminobutyric acid (GABA)ergic neurons in the parafacial zone (Anaclet et al, 2014), the ventrolateral periaqueductal gray (Weber et al, 2015;Weber et al, 2018), the ventral tegmental area (VTA) (Yang et al, 2018;Yu et al, 2019), or adenosine A 2A receptor-expressing neurons in the striatum (Oishi et al, 2017;Yuan et al, 2017) specifically promotes non-rapid eye movement (NREM) sleep, whereas subgroups of GABAergic neurons in the lateral hypothalamus (Jego et al, 2013;Konadhode et al, 2013;Tsunematsu et al, 2014) and the zona incerta (Liu et al, 2017) promote both REM and NREM sleep. With the exception of nitrergic/ glutamatergic neurons in the median and medial preoptic area that are excited by external warmth (Harding et al, 2018), the vast majority of sleep-promoting neuronal populations are GABAergic, and their sleep-promoting effects are likely mediated by the inhibition of wake-promoting populations. Because some sleep-promoting GABAergic neurons have been shown to be preferentially active during sleep (Anaclet et al, 2014;Hassani et al, 2009), an important question is whether there are excitatory sleep-active neurons that provide input to these GABAergic sleep neurons.…”

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

“…Nevertheless, and even allowing for the high sleep-wake fragmentation that appears in LPO-DGal mice, we find that LPO galanin neurons are dispensable for achieving baseline NREM sleep. But given that there are mixed populations of PO GABA (galanin and other peptide-expressing types) that induce NREM sleep (49,64); and that glutamate/NOS1 cells in MPO/MnPO can induce both NREM sleep and body cooling (31), perhaps this is not surprising Within the PO hypothalamic area, galanin-expressing neurons have quite different functions: galanin neurons coordinate parental behavior (motor, motivational, social) and mating (69,70), as well as temperature and sleep (49,56). We cannot rule out if one type of LPO galanin neuron increases NREM delta power, and another promotes chronic cooling.…”

“…cFOS-dependent activity-tagging revealed that after sleep deprivation, reactivating the tagged neurons in the preoptic area induced both NREM sleep and body cooling (26). Indeed, NREM sleep induction and core body cooling are linked by common preoptic circuitry (31), and about 80% of brain cortex temperature variance correlates with sleep-wake states (32). On entering NREM sleep, the neocortex of rats and mice cools rapidly (33,34).…”